Sequential immunization with antigens from different strains of HIV‐1, influenza viruses or dengue viruses induced cross‐neutralizing antibodies and enhanced the antibody responses against previous antigens. The characteristics of neutralizing antibodies induced by sequential immunization with different types of human papillomavirus (HPV) L1 virus‐like particles (L1VLPs) are unclear. In this study, mice were primed with one or two types (HPV‐16 or HPV16/18) of L1VLPs, then boosted sequentially with HPV6/18/45/11/31/58 or HPV6/45/11/31/58 L1VLPs, and sera were analyzed with HPV pseudovirus‐based neutralization assay. The results showed that neutralizing activities against earlier immunized vaccine types were enhanced gradually by subsequent immunizations, and low levels of neutralizing activities against nonvaccine types (HPV33/35/52/59/68) were also observed. After absorbing the immune sera with vaccine‐type (HPV16/18/45) L1VLPs, neutralizing activities against tested priming and boosting types (HPV16/18/58) decreased significantly, and that against nonvaccine type (HPV‐33) was also partially eliminated. Moreover, neutralizing activities against vaccine types (HPV16/58) were significantly reduced after absorbing with nonvaccine‐type VLPs (HPV33/52). These data suggest that cross‐neutralizing epitopes exist among different HPV L1VLPs. The cross‐neutralizing activities against nonvaccine types and the enhanced neutralizing activities against earlier immunized vaccine types may result from sequential boosting with these cross‐neutralizing epitopes. These observations support early vaccination with more types of L1VLPs derived from HPVs that cause a serious threat to the population.
The continuously emerging of severe acute respiratory syndrome coronavirus‐2 variants of concern (VOCs) led to a decline in effectiveness of the first‐generation vaccines. Therefore, optimized vaccines and vaccination strategies, which show advantages in protecting against VOCs, are urgently needed. Here we constructed an optimized DNA vaccine plasmid containing built‐in CpG adjuvant, and designed vaccine candidates encoding five forms of antigens derived from Wuhan‐Hu‐1. The results showed that plasmid with receptor binding domain (RBD) dimer‐Fc fusing antigen (2RBD‐Fc) induced the highest level of RBD‐specific IgG and neutralizing antibodies in mice. Then 2dRBD‐Fc and 2omRBD‐Fc vaccines, respectively derived from delta and omicron VOCs, were constructed. The 2dRBD‐Fc induced potent humoral and cellular immune responses, while the immunogenicity of 2omRBD‐Fc was low. We also observed that sequential immunization with 2RBD‐Fc, 2dRBD‐Fc and 2omRBD‐Fc effectively elicited neutralizing antibodies against each immunized strain, and RBD‐specific T cell responses. To be noted, the Wuhan‐Hu‐1, delta and omicron neutralizing antibody titers induced by sequential immunization were comparable to that induced by repetitive immunization with 2RBD‐Fc, 2dRBD‐Fc or 2omRBD‐Fc respectively. The results suggest that sequential immunization with DNA vaccines encoding potent antigens derived from different VOCs, may be a promising strategy to elicit immune responses against multiple variants.
The receptor-binding domain (RBD) of SARS-CoV-2 S protein is proved to be the major target of neutralizing antibodies. However, on the S protein, only a portion of epitopes in RBD can be effectively displayed with dynamic changes in spatial conformations. Using RBD fragment as antigen can better expose the neutralizing epitopes, but the immunogenicity of RBD monomer is suboptimal. Multimeric display of RBD molecules is a feasible strategy to optimize RBD-based vaccines. In this study, RBD single-chain dimer derived from Wuhan-Hu-1 was fused with a trimerization motif, and a cysteine was also introduced at the C-terminus. The resultant recombinant protein 2RBDpLC was expressed in Sf 9 cells using a baculovirus expression system. Reducing/non-reducing PAGE, size-exclusion chromatography and in silico structure prediction indicated that 2RBDpLC polymerized and possibly formed RBD dodecamers through trimerization motif and intermolecular disulfide bonds. In mice, 2RBDpLC induced higher levels of RBD-specific and neutralizing antibody responses than RBD dimer, RBD trimer and prefusion-stabilized S protein (S2P). In addition, cross-neutralizing antibodies against Delta and Omicron VOC were also detected in the immune sera. Our results demonstrate that 2RBDpLC is a promising vaccine candidate, and the method of constructing dodecamers may be an effective strategy for designing RBD-based vaccines.
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